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[Preprint]. 2024 Apr 3:2024.04.02.24304968.
doi: 10.1101/2024.04.02.24304968.

Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer

Ed M Dicks  1 , Jonthan P Tyrer  1 , Suzana Ezquina  1 , Michelle Jones  2 , John Baierl  3 , Pei-Chen Peng  3 , Michael Diaz  2 , Ellen Goode  4 , Stacey J Winham  4 , Thilo Dörk  5 , Toon Van Gorp  6 , Ana De Fazio  7 , David Bowtell  8 , Kunle Odunsi  9 , Kirsten Moysich  10 , Marina Pavanello  11 , Ian Campbell  12 , James D Brenton  13 , Susan J Ramus  14 , Simon A Gayther  2 , Paul D P Pharoah  3
Affiliations

Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer

Ed M Dicks et al. medRxiv. .

Update in

Abstract

Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls. Harmonised variant calling and quality control filtering was applied across the different data sets. We carried out a gene-by-gene simple burden test for association of rare loss-of-function variants (minor allele frequency < 0.1%) with all non-mucinous ovarian cancer, high grade serous ovarian cancer and non-high grade serous ovarian cancer using logistic regression adjusted for the top four principal components to account for cryptic population structure and genetic ancestry. Seven of the top 10 associated genes were associations of the known ovarian cancer susceptibility genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6 and PALB2 (false discovery probability < 0.1). A further four genes (HELB, OR2T35, NBN and MYO1A) had a false discovery rate of less than 0.1. Of these, HELB was most strongly associated with the non-high grade serous histotype (P = 1.3×10-6, FDR = 9.1×10-4). Further support for this association comes from the observation that loss of function variants in this gene are also associated with age at natural menopause and Mendelian randomisation analysis shows an association between genetically predicted age at natural menopause and endometrioid ovarian cancer, but not high-grade serous ovarian cancer.

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Figures

Figure 1:
Figure 1:
QQ plot for association analysis of genes with at least one case or control loss-of-function variant carrier in the non-UK Biobank data set (three genes with smalles P-values excluded)
Figure 2:
Figure 2:
Power to detect risk alleles by carrier frequency and effect size (odds ratio) at a type 1 error probability of 5×10−4. A) 2,630 cases and 15,000 controls - the carrier frequency and effect size corresponding to BRCA1, BRIP1 and RAD51C are shown for reference. B) 20,000 cases and 20,000 controls
See this image and copyright information in PMC

References

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